Erythropoietin is the most widely prescribed cytokine, yet the benefits and potential side effects of different dosing regimens are poorly understood. Clinically, it is now recognized that erythropoietin administered at high doses results in an increased probability of cancer recurrence and in patients with chronic kidney disease, an increased risk of morbidity and mortality from heart disease and stroke. However, the mechanisms that mediate this increased risk of cardiovascular disease is not known. There are two receptors for erythropoietin the homodimeric erythropoietin receptor (EPOR) and the heterodimeric beta common receptor (?CR)/EPOR. We have demonstrated that activation of the heterodimeric ?CR/EPOR only occurs with high doses of erythropoietin. Our exciting, published, preliminary data also demonstrates that the ?CR is in a complex with vascular endothelial growth factor receptor-2 and that high doses of erythropoietin activate vascular endothelial growth factor receptor-2 through the ?CR, resulting in all of the deleterious effects of vascular endothelial growth factor receptor-2 activation on the cardiovascular system. This is particularly important in patients with kidney disease since they are already at a high risk of cardiovascular disease. Moreover in advanced kidney disease cyanate derived from the high urea levels can non-enzymatically form an amide bond with erythropoietin. This carbamylated erythropoietin has no effect on hemoglobin, but still activates the heterodimeric ?CR/EPOR. To date there have been no studies that have directly measured levels of carbamylated erythropoietin or activation of the ?CR/EPOR in patients with kidney disease. Our hypothesis is that the administration of low-doses of erythropoietin more frequently will result in lower levels of total and carbamylated erythropoietin decreased activation of vascular endothelial growth factor receptor-2 via the heterodimeric ?CR/EPOR and consequently decreased inflammation and atherosclerosis. We will directly test this hypothesis by randomly allocating 100 patients with chronic kidney disease to either low- dose erythropoietin given thrice weekly or the same cumulative dose, a high-dose, administered once every 2 weeks. Our hypothesis predicts that low-dose erythropoietin will be as effective at correcting anemia, but will demonstrate less progression of carotid artery plaque, as assessed by non-contrast magnetic resonance imaging, as compared to the high-dose, erythropoietin every 2 weeks. To delineate how erythropoietin affects blood vessels, we will isolate endothelial cells from blood vessels in 20 patients who are assigned to low-dose erythropoietin and 20 allocated to high-dose erythropoietin. Within these cells we will investigate the signaling pathways that are triggered by activation of ?CR/EPOR. In a substudy of 10 subjects randomized to low-dose erythropoietin or high-dose erythropoietin, as well as 10 healthy controls receiving a single dose of high- or low-dose erythropoietin, we will determine how kidney function and dosing affects levels of total and carbamylated erythropoietin. Our study will not only provide us with a thorough understanding of the mechanism by which erythropoietin mediates the increased risk of atherosclerosis, but a clinical strategy to avoid the side effects of erythropoietin therapy and a tool to quantify the cardiovascular risk of erythropoietin and newer erythropoiesis stimulating agents by assessing activation of the heterodimeric ?CR/EPOR.